Ether derivatives of 3-piperidinopropan-1-ol as non-imidazole histamine H3 receptor antagonists

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Abstract

A series of aliphatic and aromatic ether derivatives of 3-piperidinopropan-1-ol has been prepared by four different methods. The ethers obtained were evaluated for their affinities at recombinant human histamine H3 receptor, stably expressed in CHO-K1 or HEK 293 cells. All compounds investigated show from moderate to high in vitro affinities in the nanomolar concentration range. Selected compounds were investigated under in vivo conditions after oral administration to mice. Some proved to be highly potent and orally available histamine H3 receptor antagonists. The most potent antagonists in this series have been in vitro the 4-(1,1-dimethylpropyl)phenyl ether 19 (hH3R Ki = 8.4 nM) and in vivo the simple ethyl ether 2 (ED50 = 1.0 mg/kg).

Graphical abstract

A series of asymmetrically ether derivatives of 3-piperidino-1-ol was prepared and evaluated as histamine H3 receptor antagonists. The most potent compounds were in vitro 19 (hKi = 8.4 nM) and in vivo 2 (ED50 = 1.0 mg/kg).

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Introduction

Histamine is a biogenic amine with multiple physiological activities and since 1907, when it was first synthesized, is still in the centre of general interest.1 Its important physiological role is attributed to four known receptor subtypes: H1–H4. The third histamine receptor (H3R) acts as an autoreceptor inhibiting the synthesis and the release of histamine upon activation. The H3R occurs also as heteroreceptor modulating the release of a number of neurotransmitters including acetylcholine, dopamine, glutamate, noradrenaline and others.2 The molecular structure of this receptor was unknown until 1999 when it was published by Lovenberg et al.3 The H3R shows functional constitutive activity in vivo, polymorphisms and multiple splice variants that differ across species (for review, see4, 5).

H3R antagonists could be useful for the treatment of a wide range of central nervous system (CNS) disorders including attention-deficit hyperactivity disorder (ADHD), Alzheimer’s disease, schizophrenia, epilepsy as well as sleep disorders (narcolepsy) or obesity.6, 7, 8, 9 Numerous histamine H3R ligands have been preclinically evaluated and may be some, at least one, have even entered clinical stages, for example, GT-2331 (cipralisant formerly perceptin; entered phase II clinical studies for ADHD).9, 10 So far, none of the H3R antagonists has been brought into the market. Thus, much effort is focused on understanding H3 receptor (patho)physiology and on the design of selective and potent H3R ligands.

The first H3R antagonists were 4(5)-substituted imidazoles (for review, see9, 11). However, due to well-known unfavourable imidazole-based properties (CYP 450 binding,12 potential lack of selectivity towards histamine H3/H4 receptors,13 and lower affinity for cloned human H3R than that for, e.g., rodent14) the actual focus is on the development of non-imidazole compounds (for review, see11(a), 15).

The aromatic imidazole moiety was successfully replaced among others by an aliphatic piperidine, pyrrolidine or piperazine ring (for review, see11(a), 15). Such compounds (different to endogenous ligand) may give a chance for enhanced selectivity, that is, for low binding at H4 receptors. This could be confirmed by other investigations and there are known non-imidazole H3R ligands inactive at the H4 receptor.13, 18(a)

Some of the non-imidazole H3R antagonists have entered clinical trials, for example, Abbott Laboratories ABT-239, which has been described as a promising agent for the treatment of a variety of CNS disorders (ADHD, Alzheimer’s disease and schizophrenia)16, 17 (Fig. 1).

Among classical approaches industrial high-throughput screenings (HTS) led to the identification of new non-imidazole ligands possessing the 3-piperidinylpropyloxy motif.18 This motif is also present in the compound chosen as the lead structure (FUB 637) for the work presented here (Fig. 2). In 2001, Meier et al. published the results of ring replacements in piperidine analogues of the known imidazole-based H3R antagonists.19 Compound FUB 637 was one of the most interesting ligands with comparable in vitro and in vivo potency to its imidazole analogue, FUB 153 (Fig. 2).

As an extension of our previous work in the non-imidazole field 20, 21, 22 we have prepared a series of ether derivatives of 3-piperidinopropan-1-ol with general structure presented in Figure 3. All compounds were screened for their affinities at the human histamine H3 receptor stably expressed in CHO-K1 cells or HEK 293. The in vivo potencies of selected compounds were also investigated.

Section snippets

Chemistry

The novel ether derivatives 219 were synthesized by four different methods as outlined in Scheme 1. 3-Piperidinopropan-1-ol (1) was obtained from piperidine and 3-chloropropan-1-ol by the method described previously.20

Ethers 2, 46 and 1417 were synthesized by the Johnstone and Rose procedure.23 The alcohol 1 and appropriate alkyl halide were added to powdered KOH stirred in dimethylsulfoxide (DMSO) and usually heated in an oil bath (50 or 90 °C).

Ethers 3, 7, 8 and 1013 were prepared under

In vitro binding assay at cloned human histamine H3 receptors

The affinities of compounds were determined by measuring the displacement curves of [125I]iodoproxyfan binding at human histamine H3 receptors expressed in CHO-K1 or HEK 293 cells stably transfected with the full-length coding sequence of the hH3R, as described previously (Table 2).27, 28

Tested compounds showed different affinities from high (2 and 3) to low (19) nanomolar concentration range. In the aliphatic series (compounds 24 and 8) elongation of the carbon chain led to an increase in H3R

Conclusions

In this study, we report on novel potent histamine H3 receptor ligands. These compounds are ether derivatives of 3-piperidinopropan-1-ol. They proved to be histamine H3 receptor ligands investigated in [125I]iodoproxyfan binding studies on the human histamine H3 receptor and showed affinities from high to low nanomolar concentration range. In vivo screening of selected compounds showed the highest antagonist potency for the ethyl ether derivative 2.

Ether derivatives 1719 are highly potent both

General procedures

Melting points were determined on a MEL-TEMP II apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-Merkury 300 MHz spectrometer in DMSO-d6. Chemical shifts are expressed in parts per million downfield from internal tetramethylsilane as reference. Data are reported in the following order: multiplicity (br, broad; def, deformed; s, singlet; d, doublet; dd, doublet of doublets; t, triplet; m, multiplet ∗ or massif ∗∗ (∗, the centre of the chemical shift is given and ∗∗, the

Acknowledgements

We gratefully thank Mrs. M. Kaleta for help in preparing compounds 7, 10, 11 and 13. This work was supported by the Biomedical and Health Research Programme (BIOMED) of the European Union, the Fonds der Chemischen Industrie, Verband der Chemischen Industrie, Frankfurt am Main, Germany and the Polish State Committee for Scientific Research, Grant No. 6 P05F 013 20, respectively.

References and notes (34)

  • A.A. Hancock et al.

    Life Sci.

    (2003)
  • M.B. Passani et al.

    Trends Pharmacol. Sci.

    (2004)
  • J.M. Witkin et al.

    Pharmacol. Ther.

    (2004)
  • C. Liu et al.

    Mol. Pharmacol.

    (2001)
  • C. Shah et al.

    Bioorg. Med. Chem. Lett.

    (2002)
    C. Chai et al.

    Bioorg. Med. Chem. Lett.

    (2003)
    R. Apodaca et al.

    J. Med. Chem.

    (2003)
    C.A. Dvorak et al.

    J. Med. Chem.

    (2005)
  • R.A.W. Johnstone et al.

    Tetrahedron

    (1979)
  • X. Ligneau et al.

    Br. J. Pharmacol.

    (2000)
  • M. Garbarg et al.

    J. Pharmacol. Exp. Ther.

    (1992)
  • A. Windaus et al.

    Chem. Ber.

    (1907)
  • S.J. Hill et al.

    Pharmacol. Rev.

    (1997)
  • T.W. Lovenberg et al.

    Mol. Pharmacol.

    (1999)
  • R. Leurs et al.

    Nat. Rev. Drug Disc.

    (2005)
  • L.F. Alguacil et al.

    Curr. Drug Targets—CNS Neurol. Disorders

    (2003)
  • H. Stark et al.

    Mini-Rev. Med. Chem.

    (2004)
  • ...
  • H. Stark

    Expert Opin. Ther. Patents

    (2003)
    M.J. Tozer et al.

    Expert Opin. Ther. Patents

    (2000)
    H. Stark et al.

    Prog. Med. Chem.

    (2001)
  • S. Rednič

    Croat. Med. J.

    (1999)
    R. Yang et al.

    Pharmacology

    (2002)
  • Cited by (0)

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